The present invention relates to a process for preparing alkali salts of cephalosporin C.
Cephalosporin C based antibiotics have been extensively used in inhibiting most Gram positive cocci bacteria and most Gram negative bacilli bacteria, and are particularly effective for patients who are sensitive to penicillin antibiotics.
A variey of cephalosporin C based antibiotics are synthesized from its intermediate, 7-aminocephalosporanic acid (briefly referred to as 7-ACA) by replacing the amino group at the 7-position with different substituents. The intermediate, 7-ACA, is synthesized from the sodium salt of cephalosporin C by the enzymatic action of D-amino acid oxidase and glutaryl amidase.
Aqueous solutions of cephalosporin C are unstable at a pH value less than 2 at 25.degree. C. where they convert into their ketone and thus lose their ability to inhibit the growth of bacteria. At a pH higher than 9, they convert into desacetyl cephalosporin C which only demonstrates 20% of the biological activity of cephalosporin C.
Cephalosporin C is produced from Cephalosporium using the fermentation method. As the concentration of the cephalosporin C in the fermentation broth is very low (about 2%), a zinc ion-containing solution is usually added to precipitate the cephalosporin C and recover the zinc salts. The zinc salts are then converted into sodium salts of cephalosporin C for use.
As the solubility of the zinc salts of cephalosporin C in water is low, the conventional method for converting zinc salts into sodium salts involves mixing solid zinc salts of cephalosporin C with acid form cation-exchange resins and an appropriate amount of water. By this mixing, the aqueous solution produced by the exchange of a portion of the dissolved zinc ions of cephalosporin C with the acid form cation-exchange resins will have the lower pH value of the aqueous solution. This improves the solubility of the cephalosporin C zinc salts. According to the conventional method, the reaction of the zinc salt with cation-exchange resin reaches equilibrium when the pH value is 2.0, the concentration of the cephalosporin C is 3.5%, and the concentration of the zinc salts at the equilibrium point is about 0.2%. The solution is then filtered, and separated with acid form cation-exchange resins. The filtrate is introduced into a Na form cation-exchange resin to remove the residual zinc ions. Clearly the above conventional method is quite complicated and time-consuming.